Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome.
The ATP7A gene encodes a copper-transporting ATPase. Mutations in this gene result in two clinically distinct X-linked inherited disorders: Menkes disease and occipital horn syndrome (OHS). We identified a single exon skipping in the ATP7A transcript in cells from the affected proband, affected cousins and obligate carriers in a family with OHS. Genomic sequencing identified an A-->T transversion at the +3 position in the splice donor site of intron 10 (gtaaagt-->gttaagt) in all affected individuals and the obligate female carriers. This mutation results in the constitutive skipping of exon 10 and creates an in-frame deletion of transmembrane domains 3 and 4 (78 amino acids) in the mature transcript. The exon 10-skipped transcript is present in low amounts as an alternatively spliced product in normal individuals. Immunocytochemical assay shows that these two protein products have different subcellular distributions: the major form is concentrated in the perinuclear Golgi system while the minor form (as the only form in this family with OHS) is co-localized with the endoplasmic reticulum-resident BiP protein (GRP78). These findings indicate that endoplasmic reticulum localization only of a variant ATP7A protein is insufficient to effect normal copper transport.
Qi
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M
Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
Byers
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PH
D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics*; D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D027682:Cation Transport Proteins; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D017931:DNA Primers; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D011993:Recombinant Fusion Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases